Biomedical subjects

Paresh Vyas

Publications and source records attributed to Paresh Vyas.

3 recordsLinked to original sources

PubMed2026

Retrotransposable element derepression distinguishes DNMT3A-mutant from TET2-mutant clonal haematopoiesis.

Clonal haematopoiesis (CH) is driven by somatic mutations in haematopoietic stem cells that generate clonal populations detectable in peripheral blood and is present in 10-20% of individuals over the age of 65. Mutations in DNMT3A and TET2 are the most common drivers and have been linked to inflammatory phenotypes and increased risk of haematologic and cardiovascular disease. However, the cell-intrinsic mechanisms connecting these mutations to inflammatory signalling remain incompletely understood. Because retrotransposable elements (RTEs) are epigenetically regulated and can activate innate immune pathways when derepressed, we hypothesised that RTE reactivation may represent a mutation-specific mechanism linking clonal haematopoiesis driver mutations to inflammatory pathways. We analysed RTE expression and clonal burden in peripheral blood mononuclear cell (PBMC) samples from 56 individuals with CH and 12 non-CH controls using integrated genomic and transcriptomic approaches, with complementary validation by TARGET-seq across haematopoietic lineages. High variant allele frequency (VAF; > 10%) DNMT3A-mutant clones exhibited widespread derepression of RTEs, particularly LINE and LTR families, whereas TET2-mutant clones showed a trend towards reduced RTE expression relative to controls. Transcriptomic analyses revealed that DNMT3A high-variant allele frequency clones with elevated RTE expression were enriched for inflammatory signalling pathways, including TNF-α/NF-κB signalling, interferon responses, and senescence-associated signatures. In contrast, TET2-mutant clones lacked these RTE-associated inflammatory signatures and instead showed enrichment of oxidative phosphorylation, reactive oxygen species signalling, and a mechanistic target of rapamycin complex 1 pathway. These findings were reproduced in an independent cohort. Collectively, our results highlight mutation-specific inflammatory mechanisms in clonal haematopoiesis and provide a foundation for future functional and preclinical studies to determine whether modulation of RTE activity can influence the inflammatory phenotype of DNMT3A-mutant CH and represent a potential therapeutic strategy.

DNMT3A↗

PubMed2026

Magrolimab Plus Azacitidine Versus Placebo Plus Azacitidine in Patients With Untreated Higher-Risk Myelodysplastic Syndromes: The Phase III ENHANCE Study.

PURPOSE: To evaluate the efficacy and safety of the cluster of differentiation 47-targeted antibody magrolimab plus azacitidine (Magro/Aza) versus azacitidine alone in treatment-naïve patients with higher-risk myelodysplastic syndromes (MDS) in the phase III ENHANCE study (ClinicalTrials.gov identifier: NCT04313881). METHODS: Based on the Revised International Prognostic Scoring System, patients with intermediate- to very-high-risk MDS were randomly assigned to receive Magro (1 mg/kg on days [D]1 and 4; 15 mg/kg on D8; 30 mg/kg on D11 and D15, and then once per week for five doses, followed by 30 mg/kg maintenance doses once every 2 weeks)/Aza (75 mg/m2 daily on D1-7 or on D1-5 and 8-9 in 28-day cycles) or matched placebo plus azacitidine (Placebo/Aza). Dual primary end points were complete remission (CR) rate (per 2006 International Working Group criteria) and overall survival (OS). RESULTS: At final analysis, 539 patients were randomly assigned to Magro/Aza (n = 268) or Placebo/Aza (n = 271) arms. Baseline characteristics were generally well balanced between treatment arms. In the Magro/Aza versus Placebo/Aza arms, the CR rate was 21.3% versus 23.6% (odds ratio, 0.876 [95% CI, 0.585 to 1.312]; P = .5218), and median OS was 15.9 versus 18.6 months (hazard ratio, 1.203 [95% CI, 0.947 to 1.528]; P = .1299). Magro/Aza had a higher incidence of grade ≥3 adverse events (AEs; 92.8% v 79.2%), AE-associated study drug discontinuations (24.0% v 12.1%), serious AEs (71.9% v 51.5%), and fatal AEs (15.2% v 9.8%) versus Placebo/Aza. CONCLUSION: ENHANCE did not meet the primary end points of CR rate and OS, and showed more frequent severe AEs in patients treated in the Magro/Aza arm.

Humans↗

PubMed2026

MYB activity drives emergent enhancer activation and enhancer-promoter interactions in acute lymphoblastic leukemia.

Aberrant enhancer usage is a defining feature of oncogenic transcriptional reprogramming. Therapeutic strategies that disrupt enhancer-driven gene regulation may offer new treatment avenues. MYB is a key hematopoietic transcription factor that is frequently dysregulated in a broad range of cancers and plays a critical role in sustaining malignant cell states, including in aggressive leukemia subtypes such as KMT2A-rearranged leukemias. The molecular mechanisms by which it maintains oncogenic transcription remain incompletely understood. Here, we investigate the role of MYB in directing pathological enhancer activity to drive oncogene expression in leukemia. Using high-resolution Micro Capture-C, we show that upon MYB degradation, highly defined enhancer-promoter interactions at MYB binding sites are lost, correlating with the significant downregulation of target gene expression. When anchored to a gene desert region, the Myb transactivation domain (MybTA) is sufficient and necessary for the nucleation of an enhancer-like region. Critically, long-range chromatin interactions are established up to 400 kb away from where MybTA is anchored. This results in the activation of transcription from distal cryptic elements, which is reduced or abolished in the presence of point mutations that disrupt its interaction with the coactivators P300/CBP. All these results indicate that MYB activity alone is sufficient to generate an enhancer, inducing transcription through precise enhancer-promoter cross talk, and identify the MYB-P300/CBP axis as a therapeutically actionable vulnerability in enhancer-driven malignancies.

Promoter Regions, Genetic↗